title: Primary bone marrow mesenchymal stromal cells rescue the axonal phenotype of Twitcher mice.
abstract: Krabbe's disease (KD) is a demyelinating disorder caused by the deficiency of lysosomal galactocerebrosidase (GALC), affecting both the central (CNS) and the peripheral nervous system (PNS). A current therapy, hematopoietic stem cell transplantation (HSCT), is ineffective at correcting the PNS pathology. We have previously shown that systemic delivery of immortalized bone marrow-derived murine mesenchymal stromal cells (BM-MSCs) diminishes the neuropathology of transplanted Twitcher mice, a murine model of KD. In this study, to move one step closer to clinical application, the effectiveness of a systematic delivery of primary BM-MSCs to promote recovery of the Twitcher PNS was assessed. Primary BM-MSCs grafted to the Twitcher sciatic nerve led to increased GALC activity that was not correlated to decreased psychosine (the toxic GALC substrate) accumulation. Nevertheless, BM-MSC transplantation rescued the axonal phenotype of Twitcher mice in the sciatic nerve, with an increased density of both myelinated and unmyelinated axons in transplanted animals. Whereas no increase in myelination was observed, upon transplantation an increased proliferation of Schwann cell precursors occurred. Supporting these findings, in vitro, BM-MSCs promoted neurite outgrowth of Twitcher sensory neurons and proliferation of Twitcher Schwann cells. Moreover, BM-MSCs expressed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and promoted increased BDNF synthesis by neighboring Schwann cells. Besides their action in neurons and glia, BM-MSCs led to macrophage activation in Twitcher sciatic nerves. In summary, primary BM-MSCs diminish the neuropathology of Twitcher sciatic nerves by coordinately affecting neurons, glia, and macrophages.
authors.affiliation: Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal.
authors.forename: Catarina Oliveira
authors.initials: CO
authors.lastname: Miranda
authors.forename: Carla Andreia
authors.initials: CA
authors.lastname: Teixeira
authors.forename: Vera Filipe
authors.initials: VF
authors.lastname: Sousa
authors.forename: Telma Emanuela
authors.initials: TE
authors.lastname: Santos
authors.forename: Márcia Almeida
authors.initials: MA
authors.lastname: Liz
authors.forename: Ana Maio
authors.initials: AM
authors.lastname: Marques
authors.forename: Perpétua
authors.initials: P
authors.lastname: Pinto-do-Ó
authors.forename: Mónica Mendes
authors.initials: MM
authors.lastname: Sousa
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D011609:Psychosine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C019277:brain-derived growth factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011609:Psychosine; D020932:Nerve Growth Factor